Daily low-dose aspirin (81 mg) therapy is the gold standard for primary and secondary prevention of atherothrombotic disease. The American Academy of Chest Physicians recommends that all men over 45 and women over 50 with e1 cardiovascular disease risk factor engage in low-dose aspirin therapy1. Aspirin is an irreversible inhibitor of platelet and vascular cyclooxygenase (COX) I and II. At low doses aspirin acetylates platelet COX-1 in the presystemic (portal) circulation2 inhibiting platelet production of the potent aggregating agent and vasoconstrictor thromboxane A2 (TXA2) for the life of the platelet (~10 days). Our recently published data [and manuscript currently in preparation] demonstrate that platelet inhibition with either chronic low-dose aspirin (81mg daily) or clopidogrel 1) consistently and significantly attenuates reflex cutaneous vasodilation (VD) in middle-aged (5813 years) human skin3;however the precise mechanisms underlying these responses are unclear as are the functional consequences, if any. Considering the widespread use of low-dose aspirin and other platelet inhibitors, and the unexpected potential for these therapies to impair thermoregulatory VD, further research into the underlying vascular signaling mechanisms is needed. Our newly published data show that vascular inhibition of COX is not the mechanisms by which low-dose aspirin is attenuating reflex VD. Furthermore, our preliminary data shows that significantly attenuated reflex VD occurs regardless of the mechanisms of platelet inhibition (low-dose aspirin platelet COX-1 or clopidogrel platelet ADP-receptor). There are several putative mechanisms that may explain our observations including: 1) platelets may release substances that directly stimulate cutaneous VD pathways during reflex cutaneous VD, and/or 2) decreased whole blood viscoelasticity induced by platelet inhibitors may decrease the shear stimulus on the cutaneous microvasculature resulting in attenuated VD. The studies presented in this proposal systematically characterize the mechanisms and functional effects of changing whole blood viscoelastic properties on cutaneous vasodilatory responsiveness using a several stimuli to alter microvascular shear (cutaneous reactive hyperemia and slow local heating). [We aim to independently alter whole blood viscosity while inducing cutaneous VD via shear-stress mechanisms with and without the localized sympathetic adrenergic control intact (bretylium iontophoresis).] Finally, we will examine potential functional consequences of asprin/clopidogril-induced impairments in thermoregulatory effector mechanisms during exercise in the heat. PUBLIC HEALTH RELEVANCE: Daily low-dose aspirin (81 mg) is the gold standard antiplatelet therapy for primary and secondary prevention of atherothrombotic disease. Data from our laboratory suggest that chronic low-dose aspirin therapy (81mg daily for >1year) severely attenuates reflex cutaneous vasodilation in middle-aged human skin (5813 years). Our research could uncover a previously undocumented effect of aspirin and other platelet inhibitors on the control of cutaneous vasodilation and thus on the ability to regulate core body temperature during heat stress. This finding would be important to the many people routinely taking daily low-dose aspirin and their physicians. Also, the project will examine the mechanisms underlying the effect of these drugs to further our understanding of the control of skin blood flow and the decrement in the cutaneous vasodilation response to heat stress observed in older people.